Published online Dec 28, 2018. doi: 10.3748/wjg.v24.i48.5477
Peer-review started: August 27, 2018
First decision: October 24, 2018
Revised: November 8, 2018
Accepted: November 13, 2018
Article in press: November 13, 2018
Published online: December 28, 2018
The receptor interacting protein kinase-3 (RIP3) inhibition in various non-alcoholic fatty liver disease (NAFLD) models has shown varied results. The underlying mechanism associated with these diverse outcomes is still not clear. The evaluation of necroptosis signaling molecules in NAFLD might provide a useful therapeutic target.
Previous studies report that in high fat (HF)-induced NAFLD, RIP3 deletion exacerbated fatty change, inflammation, fibrosis, and apoptosis. However, in the methionine choline deficient diet-induced NAFLD model, these changes were not observed. The reason for the varied results associated with RIP3 deletion in different NAFLD models is unknown.
To validate the effects of RIP3 deletion in NAFLD and to clarify the mechanism of action.
Wild-type and RIP3 knockout mice were fed HF and normal chow diets for 12 wk. The body weight was assessed weekly. After 12 wk, the liver and serum samples were analyzed for changes. Hematoxylin & eosin staining, NAFLD Activity Score evaluation, and triglyceride quantification were performed. The changes in very-low-density lipoproteins (VLDL) secretion and inflammation markers were recorded. Primary hepatocytes were evaluated for lipid contents. HepG2 cells and U937 cells were evaluated for changes in inflammatory markers.
Our results show that RIP3 deletion is associated with exacerbated hepatic lipid contents, suppressed VLDL secretion markers, and partially suppressed inflammation.
In HF diet-induced NAFLD, RIP3 deletion is associated with increased hepatic steatosis and partially suppressed inflammation
Necroptosis signaling molecules, especially mixed lineage kinase domain-like proteins, should be further explored for its therapeutic potential in NAFLD.